1. Field of the Invention
The present invention relates to small molecules that are potent inhibitors of xcex1Lxcex22 mediated cell adhesion which could be useful for the treatment of inflammatory diseases.
2. Description of Related Art
The integrin family of proteins are heterodimeric receptors which are expressed on all cell types to mediate cell to cell binding and adhesion to extracellular matrix. The xcex22 (CD18) integrin subfamily is comprised of 3 members, xcex1Lxcex22 integrin (LFA-1, CD11a/CD18), xcex1Mxcex22 integrin (Mac-1, CD11b/CD18), and gp 150 xcex22 integrin (xcex1Xxcex22 integrin, CD11c/CD18) that are primarily expressed on leukocytes (Sanchez-Madrid et al., J. Exp. Med., 158, 1785-1803 (1983)). xcex1Lxcex22 integrin is found mostly on T and B lymphocytes, while xcex1Mxcex22 integrin is present on activated neutrophils, NK cells and some myeloid cells. The xcex1Lxcex22 integrin binds to intracellular adhesion molecules ICAM-1, 2 and 3 found on multiple cell types such as vascular endothelial cells, dendritlc cells, epithelial cells, macrophage and T lymphoblasts (Dustin et al., J. Immunology, 137, 245-254 (1986)). Recently there has been evidence presented that xcex1Lxcex22 integrin binds to ICAM-4 and a novel ligand expressed in brain telencephalin. It has been shown that the I domain or the alpha chain is the major recognition site for its ligands.
xcex1Lxcex22 integrin adhesion to ICAM-1 is necessary for immune responsiveness of T-lymphocytes to antigens, lymphocyte homing and circulation, and cell emigration to sites or inflammation (Springer, Ann. Rev. Physiol., 57, 827 (1995)). A dominant role of xcex1Lxcex22 integrin in mediating inflammatory events is shown in several different animal models of inflammatory diseases in which antibodies to xcex1Lxcex22 integrin or ICAM-1 significantly inhibit development of therapeutic end points (Rothlein et al., Kidney International, 41, G17 (1992); Iigo et al., J. Immunology, 147, 4167 (1991); Bennet et al., J. Pharmacol. and Exp. Therapeutics, 280, 988 (1997)).
Also, xcex22 integrin subfamily are thought to play a critical role in several types of inflammatory disease processes by interacting with ICAMs. Support for the importance of xcex22 integrin in mediating inflammatory responses has been demonstrated by the evidence that transendothelial migration in vitro is markedly inhibited by monoclonal antibodies against xcex22 integrin or ICAM-1 (Smith, Can. J. Physiol. Pharmacol., 71, 76 (1993)). Furthermore, blockade of xcex1Lxcex22 integrin has been shown to inhibit neutrophil influx in almost every system, including skin, peritoneum, synovium, lung, kidney, and heart. As one of the primary ligands for the xcex22 integrin, it would also be expected that blockade of ICAM-1 would inhibit the inflammatory response (Albelda et al., The FASEB Journal, 8, 504 (1994)).
Moreover, it has been shown that antibodies against xcex1Lxcex22 integrin suppress rejection after transplantation. WO 94/04188 discloses the use of monoclonal antibodies directed against xcex1Lxcex22 integrin for all transplantations, including graft vs. host or host vs. graft diseases.
The present invention relates to a compound of the formula (I): 
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from
1) hydrogen atom, or
2) a C1-6 alkyl group which may be optionally substituted
with a carboxyl group or a C1-6 alkoxycarbonyl group; R2a and R2b are independently hydrogen atom, a halogen atom, hydroxyl group, cyano group, a C1-6 alkyl group which may be optionally substituted with 1 to 3 halogen atoms, a C1-6 alkylthio group which may be optionally substituted with 1 to 3 halogen atoms, a C1-6 alkylsulfinyl group which may be optionally substituted with 1 to 3 halogen atoms, a C1-6 alkylsulfonyl group which may be optionally substituted with 1 to 3 halogen atoms, or a C1-6 alkoxy group which may be optionally substituted with 1 to 3 halogen atoms; R3 is a C1-6 alkyl group; and R4 and R5 are independently a halogen atom.
The compound of the present invention has potent inhibitory activity against xcex1Lxcex22 mediated cell adhesion, and shows excellent in vivo improvements against the unfavorable conditions caused by xcex1Lxcex22 mediated cell adhesion.
The desired compound of the present invention may exist in he form of optical isomers based on asymmetric atoms thereof, and the present invention also includes these optical isomers and mixtures thereof.
In an embodiment of the present invention, the steric configuration of a bond need not be fixed. The compound of the present invention may be a compound with a sole configuration or a mixture with several different configurations.
In a preferred embodiment of the compound (I), R1 is hydrogen atom or a C1-6 alkyl group which may be optionally substituted with carboxyl group or a C1-6 alkoxycarbonyl group, R2a and R2b are independently hydrogen atom, a halogen atom, hydroxyl group, cyano group or a C1-6 alkoxy group which may be optionally substituted with 1-3 halogen atoms, R3 is a C1-6 alkyl group, and R4 and R5 are independently a halogen atom.
In a more preferred embodiment of the compound (I), R1 is hydrogen atom or a C1-6 alkyl group, one of R2a and R2b is hydrogen atom, and the other is a halogen atom, cyano group, or a C1-6 alkoxy group which may be optionally substituted with 1-3 halogen atoms, R3 is a C1-6 alkyl group, and R4 and R5 are independently a halogen atom.
In a further preferred embodiment of the compound (I), R1 is hydrogen atom or methyl group, one of R2a and R2b is hydrogen atom and the other is bromine atom, cyano group, a C1-6 alkoxy group or trifluoromethoxy group, R3 is methyl group, R4 and R5 are chlorine atom.
In another more preferred embodiment of the compound (I), R1 is hydrogen atom or C1-6 alkyl group which may be substituted with carboxyl or C1-6 alkoxycarbonyl, one of R2a and R2b is hydrogen atom, and the other is cyano group or C1-6 alkoxy group which may be substituted with 1-3 halogen atoms.
In another further preferred embodiment of the compound (I), R1 is hydrogen atom or methyl group, one of R2a and R2b is hydrogen atom and the other is C1-6 alkoxy group or trifluoromethoxy group, R3 is methyl group, R4 and R5 are chlorine atom.
In another preferred embodiment of the compound (I), R1 is a C1-6 alkyl group which is substituted with a C1-6 alkoxycarbonyl group or carboxyl group, one of R2a and R2b is hydrogen atom, and the other is a halogen atom, cyano group, or C1-6 alkoxy group which may be optionally substituted with 1-3 halogen atoms, R3 is a C1-6 alkyl group, and R4 and R5 are independently a halogen atom.
In a more preferred embodiment of the compound (I), R3 is methyl group, and R4 and R5 are chlorine atom.
Most preferred compound of the present invention is selected from:
3-(2,6-Dichloro-4-pyrydyl)-5-(4-bromobenzyl)-1,5-dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-propoxybenzyl)-1,5-dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-ethoxybenzyl)-1,5-dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-(1,1,1trifluoromethoxybenzyl)]-5-methyl-2,4-imidazolidinedione,
3-(2,6-dichloro-4-pyrydyl)-5-[4-(1,1,1trifluoromethoxybenzyl)]-1,5-Dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-Cyanobenzyl)-5-methyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-Cyanobenzyl)-1,5-dimethyl-2,4-imidazolidinedione; and
a pharmaceutically acceptable salt of these compounds.
The compound of the present invention has potent inhibitory activity against xcex1Lxcex22 mediated cell adhesion, and also shows excellent bioavailability after oral administration which reflects the overall improvement in plasma protein binding and solubility. The compound of the present invention therefore shows excellent in viva improvements against the unfavorable conditions caused by xcex1Lxcex22 mediated cell adhesion.
The compound of the present invention may be clinically used either in a free form or in the form of pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include an acid-addition salt with an inorganic acid or an organic acid (e.g., hydrochloride, sulfate, nitrate, hydrobromide, methanesulfonate, p-toluenesulfonate, acetate), and a salt with an inorganic base, an organic base or an amino acid (e.g., triethylamine salt, a salt with lysine, an alkali metal salt, an alkali earth metal salt and the like). Pharmaceutically acceptable salts also include an intramolecular salt thereof, or a solvate or hydrate thereof.
The compound of the present invention may be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound as defined above and a pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent may be, for example, binders (e.g., syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone), excipients (e.g., lactose, sucrose, corn starch, potassium phosphate, sorbitol, glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol, silica) disintegrators (e.g., potato starch), wetting agents (e.g., sodium laurylsulfate), and the like.
The desired compound of the present invention or pharmaceutically acceptable salts thereof may be administered either orallv or parenterally, and it may be used as a suitable pharmaceutical preparation. These pharmaceutical preparations may be in the form of a solid preparation such as a tablet, a granule, a capsule, and a powder, or in the form so a liquid preparation such as solution, suspension, and emulsion, when administered orally. When administered parenterally, the pharmaceutical preparation may be in the form of suppository, an injection preparation or an intravenous drip preparation using distilled water for injection, a physiological salt solution, an aqueous glucose solution, and so on, and an inhalation by a conventional process.
The dose of the desired compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on an administration method, age, sex, body weight, and condition of a patient, but, in general, the daily dose is preferably about 0.1 to 100 mg/kg/day, particularly preferably 1 to 100 mg/kg/day.
The compound of the present invention can be used for treating or preventing xcex1Lxcex22 adhesion mediated conditions in a mammal such as a human.
The compound of the present invention may be used for treatment or prevention of numerous inflammatory diseases such as rheumatoid arthritis, asthma, allergy conditions, adult respiratory distress syndrome, AIDS, cardiovascular diseases, thrombosis, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, skin inflammatory diseases (e.g., psoriasis, eczema, contact dermatitis, atopic dermatitis), osteoporosis, osteoarthritis, arteriosclerosis (including atherosclerosis), neoplastic diseases including metastasis of neoplastic or cancerous growth, wound, detaching retina, Type I diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), ophthalmic inflammatory conditions, inflammatory bowel diseases (Crohn""s disease and ulcerative colitis), regional enteritis, Sjogren""s Syndrome, and other autoimmune diseases.
The compound of the present invention may also be used for the rejection (i.e., chronic rejection and acute rejection) after transplantation, including allograft rejection (host vs. graft disease) and graft vs. host disease.
The compound of the present invention may be preferably used for treatment or prevention of psoriasis, rheumatoid arthritis, inflammatory bowel diseases (Crohn""s disease, ulcerative colitis), systemic lupus erythematosus, atopic dermatitis, Sjogren""s syndrome, and rejection after transplantation (allograft rejection and graft vs. host disease).
According to the present invention, the desired compound (I) can be prepared by the following methods:
Among the desired compound (I), a compound of the formula (I-a): 
wherein the symbols are the same as defined above, or a pharmaceutically acceptable salt thereof, can be prepared by
(1) cyclizing the compound of the formula (II): 
wherein OR6 is a hydroxyl group or a protected hydroxyl group, and the other symbols are the same as defined above, and
(2) converting the resulting cyclized compound into a pharmaceutically acceptable salt thereof by a conventional method, if desired.
When OR6 is a protected hydroxyl group, the protecting group can be selected from the conventional protecting groups for a carboxyl group (i.e., a C1-6 alkyl group, benzyl group).
The cyclization can be carried out by a conventional condensation method. For example, the cyclization of the compound (II) can be carried out in the presence of an acid or a base in a suitable solvent.
The acid can be selected from organic acids (i.e., p-toluenesulfonic acid, and trifluoroacetic acid) and inorganic acids (i.e., hydrochloric acid, sulfuric acid, and nitric acid).
The base can be selected from conventional bases such as alkali metal alkoxide (e.g., NaOEt, NaOMe).
The solvent can be selected from any one which does not disturb the cyclization reaction, for example, CH2Cl2, THF, DMF, alcohols (methanol, ethanol, etc.) or a mixture thereof. The reaction is carried out at a temperature of 0xc2x0 C. to boiling point of the solvent, preferably at 50xc2x0 C. to 100xc2x0 C.
The cyclization of the compound (II) is also carried out in the presence of a condensing reagent with or without a base in a suitable solvent or without a solvent. The condensing reagent can be selected from SOCl2 and conventional condensing reagents which can be used for a peptide synthesis, for example, BOP-Cl, BOP reagent, DCC, EDC or CDI.
The base can be selected from an organic base (e.g., DIEA, DMAP, DBU, Et3N), an alkali metal hydride (e.g., NaH, LiH), an alkali metal carbonate (e.g., Na2CO3, K2CO3), an alkali metal hydrogen carbonate (e.g., NaHCO3, KHCO3), an alkali metal amide (e.g., NaNH2), an alkali metal alkoxide (e.g., NaOMe, KOMe), a C1-6 alkyl alkali metal salt(e.g., n-BuLi, t-BuLi), an alkali metal hydroxide (e.g., NaOH, KOH), an alkaline earth metal hydroxide (e.g., Ba(OH)2), and the like.
The solvent can be selected from any one which does not disturb the cyclization reaction, for example, CH2Cl2, THF, DMF or a mixture thereof. The reaction is carried out at a temperature of 0xc2x0 C. to room temperature, preferably at room temperature.
Among the desired compound (I), a compound of the formula (I-b): 
wherein R11 is a C1-6 alkyl group which may be optionally substituted with carboxyl group or a C1-6 alkoycarbonyl group and the other symbols are the same as defined above, or a pharmaceutically acceptable salt thereof, may be prepared by:
(1) alkylating the compound (I-a),
(2) hydrolyzing the resulting compound, if necessary, and
(3) converting the resulting compound into a pharmaceutically acceptable salt thereof by a conventional method, if further desired.
(1) Alkylation Reaction
The alkylation reaction can be carried out by reacting the compound (I-a) with the compound of the formula (III):
R11xe2x80x94Xxe2x80x83xe2x80x83(III)
wherein X is a leaving group and R11 is the same as defined above.
The leaving group X can be selected from conventional leaving groups, such as a halogen atom (e.g., chlorine, bromine, iodine) and an alkylsulfonyloxy group or an arylsulfonyloxy group (e.g., methylsulfonyloxy group, p-tolylsulfonyloxy group).
The alkylation reaction can be carried out in the presence of a base in a suitable solvent.
The base can be selected from conventional bases such as alkali metal hydride (i.e., NaH, KH), alkali metal alkoxide (i.e., NaOMe, NaOEt) and alkali metal amide (i.e., NaNH2, LDA, KHMDS).
The solvent can be selected from any one which does not disturb the condensation reaction, for example, DME, THF, DMF, HMPA or a mixture thereof. The reaction is carried out at a temperature of xe2x88x9278xc2x0 C. to room temperature.
(2) Hydrolysis Reaction
The compound (I-b) wherein R11 is a C1-6 alkyl group substituted with carboxyl group can be prepared by hydrolyzing the compound (I-b) wherein R11 is a C1-6 alkyl group substituted with a C1-6 alkoxycarbonyl group. The hydrolysis can be carried out by a usual procedure, for example, by treating the compound with a base in a suitable solvent. The base can be selected from conventional inorganic bases such as LiOH, NaOH and KOH. The solvent can be selected from any one which does not disturb the hydrolyzing reaction, for example, THF, MeOH, EtOH, H2O or a mixture thereof. The reaction can be carried out at a temperature of xe2x88x9278xc2x0 C. to 50xc2x0 C., preferably at a temperature of 0xc2x0 C. to room temperature.
Among the desired compound (I), the compound of the formula (I-c): 
or a pharmaceutically acceptable salt thereof, wherein R21 is a C1-6 alkoxy group and the other symbols are the same as defined above, can be prepared by alkylating a compound of the formula (I-d): 
wherein the symbols are the same as defined above, and converting into the pharmaceutically acceptable salt, if desired.
The alkylation reaction can be carried out in a similar manner as described in Method B (l) using a suitable halogenated C1-6 alkane (e.g., methyl iodide, benzyl bromide) in the presence of a base (e.g., Et3N, DIEA, NaHCO3, KHCO3, Na2CO3, K2CO3, KHCO3, CsCO3) at a temperature of 0xc2x0 C. to 50xc2x0 C. in an organic solvent (e.g., CH2Cl2, THF, DMF, CH3CN, toluene).
The compound (I) wherein R2a and/or R2b are hydroxyl groups can be prepared by the demethylation of the compound (I) wherein R2a and/or R2b methoxy group. The demethylation reaction can be carried out by a conventional method, for example, a treatment with BBr3 or HBr at a temperature of xe2x88x9278xc2x0 C. to 50xc2x0 C. in a suitable solvent (e.g., AcOH, water).
The starting compound of the formula (II) can be prepared by the following scheme: Scheme 1. 
(In the Scheme 1, the symbols are the same as defined above.)
Step 1: The compound (VII) can be prepared by reacting the compound (VIII) with pivalaldehyde. The reaction can be carried out in the presence or absence of an acid or an acidic salt in a suitable solvent or without a solvent. The acid can be selected from conventional inorganic acid such as HCl, H2SO4. The acidic salt can be selected from a salt of a strong inorganic acid and a weak inorganic base such as MgSO4. The solvent can be selected from any one which does not disturb the reaction, for example, toluene, DME, DMF, THF, CH2Cl2 or a mixture thereof. The reaction can be carried out, for example, at a temperature of 0xc2x0 C. to room temperature.
Step 2: The compound (IV) can be prepared by 1) reacting the compound (VII) with the compound (VI), and 2) hydrolyzing the resulting compound.
The reaction of the compound (VII) and the compound (VI) can be carried out in the presence of a base in a suitable solvent or without a solvent. The base can be selected from conventional bases such as alkali metal alkoxides (e.g., t-BuOK, MeONa, EtONa) and alkali metal amides (e.g., LDA, NaNH2). The solvent can be selected from any one which does not disturb the coupling reaction, for example, toluene, DME, DMF, THF, CH2Cl2 or a mixture thereof. The reaction can be carried out, for example, at a temperature of xe2x88x9278xc2x0 C. to 50xc2x0 C., preferably at a temperature of xe2x88x9210xc2x0 C. to 0xc2x0 C.
Hydrolysis can be carried out in the presence of an acid in a suitable solvent or without a solvent. The acid can be selected from conventional inorganic acid such as HNO3, HCl, and H2SO4. The solvent can be selected from any one which does not disturb the reaction, for example, toluene, DME, DMF, THF, CH2Cl2 or a mixture thereof. The reaction can be carried out, for example, at a temperature of 0xc2x0 C. to room temperature.
Step 3: The compound (II) can be prepared by reacting the compound (IV) with the compound (V).
The reaction can be carried out in the presence or absence of a base in a suitable solvent or without a solvent. The base can be selected from conventional inorganic bases such as K2CO3, Na2CO3 and NaHCO3, and conventional organic bases such as pyridine, Et3N, iPr2EtN, aniline, and N,N-dimethylaniline. The solvent can be selected from anv one which does not disturb the coupling reaction, for example, toluene, DME, DMF, THF, CH2Cl2 or a mixture thereof. The coupling reaction can be carried out, for example, at a temperature of xe2x88x9278xc2x0 C. to 50xc2x0 C., preferably at a temperature of 0xc2x0 C. to room temperature.
In the present description and the claims, the C1-6 alkyl group means a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, etc., preferably one having 1 to 4 carbon atoms. The C1-6 alkoxy means a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutyloxy, etc., preferably one having 1 to 4 carbon atoms.
AcOEt: Ethyl acetate (=EtOAc)
BSA: Bovine serum albumin
DMF: Dimethyl formamide
DCM: Dichloromethane
DIEA: Diisopropylethylamine
DMSO: Dimethyl sulfoxide
Et: Ethyl
EtOH: Ethanol
HBSS: Hank""s balanced salt solution
HMPA: Hexamethylphosphoramide
HSA: Human serum albumin
KHDS: Potassium hexamethyldisilazide (=Potassium bis(trimethylsilyl)amide)
LDA: Lithium diisopropylamide
Me: Methyl
MeOH: Methanol
n-Bu: n-Butyl
Ph: Phenyl
t-Bu: tert-butyl
THF: Tetrahydrofuran
Tf: Trifluoromethanesulfonyl
TFA: Trifluoroacetic acid
The compound of the present invention is exemplified by the following examples but not limited thereby.